Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.

Abstract

Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2CNM with Dnm2CMT mouse models. Dnm2offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.